Spasticity in Multiple Sclerosis (MS)
Spasticity is a motor disorder clinically defined as a velocity-dependent increase in muscle tone resulting from hyperexcitable stretch reflexes, spasms and hypersensitivity to normally innocuous sensory stimulations. The intermittent or sustained involuntary muscle hyperactivity that characterises spasticity is associated with upper motor neurone lesions that can be located anywhere along the path of the corticospinal (pyramidal) tracts. This includes the motor pathways of the cortex, basal ganglia, thalamus, cerebellum, brainstem or spinal cord.
Spasticity in MS is characterised by stiffness in one or more muscle groups, due to over excitation. It may be accompanied by spasms, which are often painful, and controlled movement becomes difficult. Spasticity is a common feature of MS with 40-84% of patients reporting mild to severe spasticity in different studies (Barnes M P, Kent R M, Semlyen J K, McMullen K M (2003), Neurorehabil Neural Repair 17:66-70; Hemmett L, Holmes J, Barnes M, Russell N (2004), QJM 97:671-676; Rizzo M A, Hadjimichael O C, Preiningerova J, Vollmer T L (2004), Mult Scler 10:589-595; Collongues N, Vermersch P (2013), Expert Rev Neurother 13:21-25, 2013; Oreja-Guevara C, Gonzalez-Segura D, Vila C (2013), Int J Neurosci 123:400-408). Spasticity in MS is associated with a decrease in patient life quality. Current drugs used to treat spasticity include Baclofen, a GABAA agonist, Tizanidine, an alpha2 adrenergic agonist, Dantrolene, a drug that acts on muscle sarcolamella and Sativex, a cannabinoid receptor 1 (CB1) agonist. All these drugs show less than optimal control of symptoms and are accompanied by moderate to severe side effects such as sedation, muscle weakness or have the potential for abuse. Thus poor tolerance and under-treatment result in unmet needs in MS spasticity management.
Mechanisms of Spasticity
The aetiology of spasticity in MS has been relatively little studied. This is in contrast to spasticity caused by spinal cord injury, where the control of chloride homeostasis has recently been invoked as a key mechanism mediating spasticity (Boulenguez P, Liabeuf S, Bos R, Bras H, Jean-Xavier C, Brocard C, Stil A, Darbon P, Cattaert D, Delpire E, Marsala M, Vinay L (2010), Nat Med 16:302-307). A complex system of channels and transporters controls neuronal excitability versus inhibitory signalling in the spinal cord. Low intracellular chloride ion concentrations are thought to mediate inhibitory signalling and concentrations of chloride are maintained at a low level by the potassium/chloride ion transporter KCC2. At these low concentrations of chloride opening of GABAA channels and glycine channels serve to increase chloride concentrations and cause a hyperpolarising current. Following spinal cord injury KCC2 becomes downregulated, chloride levels increase and glycine mediates depolarization. While many details remain to be elucidated, the overall effect is to diminish the inhibitory signal to the muscles leading to excessive excitability, contraction and spasticity. As such, deficiency in the glycine receptor in mice leads to neurological abnormalities in early juvenille life in a mouse called the Spastic mouse (von Wegerer J, Becker K, Glockenhammer D, Becker C M, Zeilhofer H U, Swandulla D (2003), Neurosci Lett 345:45-48).
To study MS related spasticity, a chronic relapsing EAE model has been developed (Baker D, Pryce G, Croxford J L, Brown P, Pertwee R G, Huffman J W, Layward L (2000), Nature 404:84-87). Efficacy in this system was demonstrated by Baclofen, endocannabinoids and cannabinoids, and has been translated to the treatment of MS. Intriguing new evidence now points to modulatory sites on glycine channels (GlyRs) for endocannabinoids (Yevenes G E, Zeilhofer H U (2011), PLoS One 6:e23886) and these may contribute to the effect on spasticity. The functions of glycine signalling have been primarily studied in pain, however it has been shown that methanandamide, the synthetic analogue of the endogenous cannabinoid anandamide, can alleviate spasticity in the chronic relapsing EAE model (Brooks J W, Pryce G, Bisogno T, Jaggar S I, Hankey D J, Brown P, Bridges D, Ledent C, Bifulco M, Rice A S, Di Marzo V, Baker D (2002), Eur J Pharmacol 439:83-92). Studies on analogues of anandamide have identified molecules with notable anti-spastic activity in the chronic relapsing EAE model, such as VSN16 (see Visintin C, Aliev A E, Riddall D, Baker D, Okuyama M, Hoi P M, Hiley R, Selwood D L (2005), Org Lett 7:1699-1702, 2005; Hoi P M, Visintin C, Okuyama M, Gardiner S M, Kaup S S, Bennett T, Baker D, Selwood D L, Hiley C R (2007), Br J Pharmacol 152:751-764).
VSN-16 was first disclosed in WO 2005/080316 (in the name of University College London). Initial studies demonstrated that VSN16 exhibits a marked effect on spasticity in CREAE mice, providing strong evidence that a selective inhibition of spasticity is achieved without producing significant adverse CNS effects.
With regard to the involvement of glycine in spasticity mechanisms, mutations in the glycine receptor demonstrate an important role in the control of muscle tone as shown by studies in mouse strains (Oscillator, Spasmodic and Spastic). The archetypal glycine antagonist, strychnine causes severe muscle cramps. A hyperekplexic response (an exaggerated startle response to tactile or acoustic stimuli) is observed in humans with similar mutations. Similar responses have now been shown in humans with mutations in the glycine transporter GlyT2a (Rees M I, Harvey K, Pearce B R, Chung S K, Duguid I C, Thomas P, Beatty S, Graham G E, Armstrong L, Shiang R, Abbott K J, Zuberi S M, Stephenson J B, Owen M J, Tijssen M A, van den Maagdenberg A M, Smart T G, Supplisson S, Harvey R J (2006), Nat Genet 38:801-806).
The present invention seeks to provide new compounds that have therapeutic applications in the treatment of muscular disorders, particularly for controlling spasticity and/or tremors.